A possible approach to halting the progression of an active human infection with HIV would be to create a population of bone marrow-derived T cells and myeloid cells which were resistant to infection by the virus. Naturally occurring retrovirus resistance genes suggest a strategy for induction of genetic resistance, i.e., interference with virus adsorption to host cells. Interference would be accomplished by transduction of an env gene product or a secreted cellular receptor that would block the cellular or viral ligands, respectively. We postulate that transfer of an HIV env-related coding domain would allow blockade of the CD4 receptor and thus confer resistance to infection. Alternatively, transfer of soluble CD4 production to target cells would block the gp120 on infectious virus particles. Because the env gene products have been implicated in the pathogenesis of AIDS, an in vivo model in which to test this proposed mode of resistance would be highly desirable. A transgenic mouse expressing the portion of the human CD4 receptor that binds gp120 would allow assessment of the biological activity of gp120 peptides in the absence of infectious virus. Such a system potentially would provide insight into the role of gp120 in the loss of uninfected lymphocytes and allow safety testing of gp120- transducing gene therapy vectors.